DESCRIPTION: Lysosome function is essential for the normal development and good health of humans and other higher organisms. Patients with deficiencies in individual or multiple lysosomal enzymes exhibit acute and chronic health problems including mental retardation, developmental deformities, cardiac impairment, and premature death. In addition, alterations in lysosomal enzyme targeting may have important consequences in a number of widespread human illnesses including cancer and Alzheimer disease. Most lysosomal enzymes are delivered to the lysosome by the mannose 6-phosphate (M6P) dependent targeting system. In this pathway, lysosomal enzymes are phosphorylated on selected mannose residues and then bind to two M6P receptors (MPRs), the large, cation-independent M6P/IGF2 receptor and the small, cation-dependent M6P receptor. The MPRs function in concert to deliver the enzymes to lysosomes. The overall objective is to determine the relative roles of the two M6P receptors in the targeting of lysosomal proteins to the lysosome. Mutant mice and cell lines defective in one or both receptor will be evaluated for changes in lysosomal targeting. Experiments will include determining the affinity of the two receptors for enzymes bearing M6P residues and determining the subcellular distribution of the proteins and receptors. Second, structure function studies will be done on the M6P/IGF2 receptor to determine functional domains and to identify other receptor-binding proteins that may be involved in trafficking.